Tumor cells require nutrients to generate ATP and macromolecules to sustain survival and proliferation. (Ward P. S., et al., “Metabolic Reprogramming: a Cancer Hallmark even Warburg did not Anticipate”, Cancer Cell. 21(3) (2012), pp. 297-308.) Glucose and glutamine are two major sources of nutrients that tumor cells depend on. Tumor cells prefer to use glycolysis pathways, even under aerobic conditions, to metabolize glucose to produce lactic acid and ATP, the so-called Warburg's effect. In addition to glucose, many tumor cells are addicted to glutamine (“Gln”) for survival (DeBerardinis R. J., et al., “Q's Next: The Diverse Functions of Glutamine in Metabolism, Cell Biology and Cancer”, Oncogene. 29(3) (2010), pp. 313-24; Shanware N. P., et al., “Glutamine: Pleiotropic Roles in Tumor Growth and Stress Resistance”, J Mol Med (Berl). 89(3) (2011), pp. 229-36.). This amino acid can be metabolized to generate intermediates of tricarboxylic acid cycle for ATP production, as well as building blocks such as lipids and nucleotides to sustain the cell proliferation. Gln metabolism in cancer cells is regulated and cross-talks with multiple oncogenic pathways (Gao P, et al., “c-Myc Suppression of miR-23a/b Enhances Mitochondrial Glutaminase Expression and Glutamine Metabolism”, Nature. 458(7239) (2009), pp. 762-5; Durán R V, et al. “Glutaminolysis Activates Rag-mTORC1 Signaling”, Mol Cell. 47(3) (2012), pp. 349-58; Thangavelu K, et al., “Structural Basis for the Allosteric Inhibitory mechanism of Human Kidney-Type Glutaminase (KGA) and its Regulation by Raf-Mek-Erk Signaling in Cancer Cell Metabolism”, J. Proc Natl Acad Sci USA. 109(20) (2012), pp. 7705-10; Son J, et al., “Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway”, 496(7443) Nature. (2013), pp. 101-5.). (GLS1) is an essential enzyme that catalyzes the first step in glutamine metabolism, leading to the generation of glutamate and ammonia. Glutamate is also the critical substrate for glutathione synthesis, which plays important role in redox homeostasis. GLS1 is overexpressed across many tumor types, and myc up-regulates GLS1 protein level through transcriptional repression of miR-23a and miR-23b. Suppression of GLS1 with selective small molecule inhibitors may be valuable to treat different types of cancers (Wise D.R., et al., “Glutamine Addiction: a New Therapeutic Target in Cancer”, Trends Biochem Sci. 35(8) 2010, pp.427-33; Shukla K, et al., “Design, Synthesis, and Pharmacological Evaluation of Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) Analogs as Glutaminase Inhibitors”, J Med Chem. 55(23) (2012), pp. 10551-63.).
Thus, there is a need for compounds that inhibit GLS1.